Pandya Hima V et al.

IRJP 2011, 2 (12), 204-207

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407

Available online www.irjponline.com Research Article

FORMULATION, DEVELOPMENT AND EVALUATION OF DOXOPHYLLINE SUSTAINED RELEASE

MATRIX TABLET
Pandya Hima V *, Patel Akshay R2, Bodiwala Janki B1
1
1
Department of Pharmaceutics, Shree Devi College of pharmacy, Mangalore, Karnataka, India
2
Department of pharmacology, Shree Devi College of Pharmacy, Mangalore, Karnataka, India
Article Received on: 18/10/11 Revised on: 25/11/11 Approved for publication: 18/12/11

*Email: pandyahima57@gmail.com
ABSTRACT
The study was done with an objective to achieve a potential sustained and controlled release oral drug delivery system of a antiasthmatic drug, doxophylline which having
shorter half life. Hydroxypropyl methyl cellulose was used for gel forming agent. Differential scanning calorimeter (DSC) study show that drug and other excipints are
compatible with each other. The tablets were evaluated for physical characteristic like hardness, weight variation, fraibilty, and thickness. It was found that drug release rate
increased with the amount of osmogent because of the increased water uptake and hence increased driving force for drug release. Accelerated stability study was also performed
for three months indicated that optimized formulation was stable. Use of HPMC as the total matrix material significantly influenced the release rate of the drug. Addition of
different diluents like magnesium stearate and microcrystalline cellulose were used for improving flow ability and compressibility. Based on dissolution studies all the
formulations showed sustained release of drugs from the formulations.
KEY WORDS: Doxophylline, Matrix Tablet, Sustained Release, Hydroxyl Methyl Cellulose, Avicel.

INTRODUCTION of possible incompatibilities, because it shows changes in the

By using oral controlled drug delivery system can provide
continuous delivery of drugs at predictable and reproducible kinetics
throughout the GI transit. Also the systems that target the drug
delivery to a specific region within the GI tract for either local or
systemic action1. The major advantage of this category is that, in
addition to the convenience of reduced frequency of administration,
it provides blood levels that are devoid of the peak-and-valley effect
which are characteristic of the conventional intermittent dosage
regimen2.
Doxophylline [7-(1,3-dioxolane-2-methyl) theophylline], a new
methylxenthine derivative which has ability to inhibit
phosphodiesterase (PDE) and thus inhibit breakdown of cAMP
(cyclic adenosine monophosphate). Increase in cyclic AMP inhibits
activation of inflammatory cells in addition to bronchodilation.
Doxofylline is rapidly absorbed and has high tissular diffusion due
to its liposolubility. When administered orally the observed half-life
is 7 ± 0.8 hours in adults. 90% percent is metabolized in the liver.
Among the various types of cellulose ether derivatives, HPMC
polymers are popular in controlled release matrices due to their
compatibility with numerous drugs3,4. HPMC is having the
advantage that the material can go under direct compression of the
drug blended drug with HPMC is easily accomplished5. The
adjustment of the polymer concentration and the viscosity grade and
the addition of different types and levels of excipients in the HPMC
matrix can modify the drug release rate.
As the doxophylline is water soluble drug we can delay the release
rate of drug by using matrix tablet. By this technique we can
decrease the toxic effect of drug by controlling the loading dose6.
MATERIALS AND METHODS
Materials
Doxophylline and hydroxyl propyl methylcellulose K-4M (HPMC
K-4M) were received as a giftsamples from Yarrow Chem. India ltd,
India. Microcrystalline cellulose, polyvinyl pyrolidone K-90 (PVP
K-90) and magnesium stearate were generous gift samples from S.D.
fine Chem.Ltd., Mumbai (India). All other chemical and reagent
were of analytical grade and used as received.
Drug-excipients interaction studies
Assessment of possible incompatibilities between an active drug
substance and different excipients forms an important part of the
preformulation stage during the development of solid dosage form.
Differential Scanning Calorimeter (DSC) allows the fast Evaluation
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(12), 2011
appearance, Shift of melting endotherms and exotherms, and/or
variations in the corresponding enthalpies of reaction. The DSC
thermograms of pure drug doxophylline, other excipients and final
tablet were recorded. (Fig. 1) The thermal analysis was performed in
a nitrogen atmosphere at a heating rate of 10°C/min over a
temperature range of 50°C to 300°C3.
Preparation of tablets
Six different formulations of matrix tablets (F1toF6) having a batch
size of 100 tablets Containing doxophylline hydrochloride and other
additives were prepared by wet granulation method in which the
concentration of the drug was kept at 66.66% weight of the tablet
(400mg /tablet) HPMC KM, HPMC K 100 and avicel in different
proportions were used as polymers. Drug and polymers were passed
through 60 # sieve and then dry blend of drug were granulated with
PVP K-90 as a binder which was dissolved in isopropyl alcohol. The
mass was dried at 50°C and sized through 22 # sieve. Finally,
magnesium stearate were mixed as glidant, and then tablet blend was
compressed rotary tablet compression machine (Rimek Tablet
Machine, Minipress) using 16/32 mm, SC break line/plain. The
tablet formulation is given in table 1. All the formulations were
stored in the air tight container at room temperature for further
evaluations8,9.
POWDER FLOW PROPERTIES
(Table 2)
Angle of repose
The angle of repose of the mixture of the drug and excipients was
determined by fixed funnel method. The values are used in the
following equation to get the angle of repose.
Tan θ = h/r
Where, h, r and θ are the height, radius and angle of repose of the
powder pile10,11,12.
Bulk density
Accurately weighed 3 g of the sample was transferred to the
measuring cylinder of bulk density apparatus. The apparatus was
adjusted for 100 tapping and noted the final volume as tapped
volume.
Tapped density (ρt) = Weight of the powder / Tapped volume of the
powder
 Pandya Hima V et al. IRJP 2011, 2 (12), 204-207
Porosity
Porosity of the powder was determined by using formula:
Porosity = [(Vb – Vp)/ Vb] ×100.
Where Vb is the bulk volume and Vp is the true volume.
Carr’s index
The carr’s index of the powder was determined by using formula:
Carr’s index (%) = [(TBD – LBD) × 100]/TBD
Where, TBD is the total bulk density and LBD is the loose bulk
density.
EVALUATION OF TABLETS
(Table 3)
Prepared tablets were evaluated for certain physical properties like
uniformity of weight, hardness, friability and dissolution study etc.
Thickness
Thickness of the prepared matrix tablets were measured by using
screw gauge. Ten tablets from each formulation were randomly
selected and used. Thickness is expressed in millimeters.
Hardness
The hardness of the matrix tablets were measured using diametric
compression using a hardness tester (Monsanto Type).. Six tablets
from each formulation were randomly selected and used. The
average hardness and the standard deviation were calculated. It is
expressed in Kg/cm2.
Friability
Friability of the matrix tablets were determined. 10 tablets were
randomly selected, weighed and placed in the Roche Friabilator. The
apparatus was rotated at 25 rpm for 4 min. After revolutions the
tablets were dedusted and weighed again. The percentage friability
was measured using the formula,
Initial wt. of tablets – Final wt. of tablets
% Friability = ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ x 100
Initial wt. of tablets
Weight uniformity
Ten tablets were randomly selected from each batch and individually
weighed. The average weight and standard deviation of 20 tablets
was calculated.7
Accelerated stability studies
Optimized formulation were packed in blister and stored in ICH
certified stability chambers maintained at 40°C and 75% RH for
three months. The tablets were withdrawn periodically and evaluated
for drug content and release studies.
In-vitro dissolution study
In vitro drug release studies from the prepared matrix tablets were
conducted for a period of 12 hours using a six station USP XXII
type 1 apparatus at 37 ± 0.5°C and 50 rpm speed. The dissolution
studies were carried out in triplicate for 12 hours (initial 2 hours in
simulated gastric fluid and rest 10 hours in phosphate buffer of pH
6.8). At every 1-hour interval, samples of 10 ml were withdrawn
from the dissolution medium and replaced with fresh dissolution
medium to maintain the volume constant. After filtration and
appropriate dilution, the sample solution was analyzed for
doxophylline by an UV spectrophotometer at 275 nm (Shimadzu,
Japan). The amounts of drug present in the samples were calculated
with the help of appropriate calibration curves constructed from
doxophylline reference standard. Drug dissolved at specified time
periods was plotted as percent release versus time (hours) curve10.
RESULT AND DISCUSSION
Differential Scanning Calorimetry (DSC) Analysis
In order to investigate the possible physical interaction between drug
and excipients, DSC studies were carried out. DSC curves obtained
for pure doxophylline, HPMC K-4M, HPMC K-100M, PVP K-90,
Avicel, Mg. stearate and their physical mixtures are shown in Fig. 1.
Pure powdered doxophylline showed a melting endotherm at
144.56˚C. DSC scan of HPMC K-4M showed single broad
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(12), 2011
endotherm at 109.93˚C due to melting whereas during scanning of
HPMC K-100M, a broad endotherm ranging from 89.56°C was
observed. DSC thermo grams of physical mixture of drug and
excipients showed the melting peak of the drug at 143.50°C and
broad endothermic peak at 122.58˚C due to melting of HPMC.
Physical mixture of all above ingredients showed their identical
peaks at defined temperature range. Presence of all peaks indicates
that all ingredients are compatible with each other and THP forms
matrix with HPMC K-4M and HPMC K-100M.
Powder flow properties
The results of preformulation parameters for formulated physical
mixtures of all batches are shown in table 2. The flowability of the
polymers was found to be quite good according to the flow
properties. Angle of repose ranges from 20.18 to 29.39°, bulk
density ranges from 0.310 to 0.381 g/cm3, % Compressibility ranges
from 12.93 to 14.10%.
Physicochemical properties
The physicochemical properties of the formulated batches are
shown in the table 3. The hardness of the matrix tables was found in
the range of 7.20-8.6 kg/cm2. Thickness ranges from 3.28-3.96 mm,
friability ranges from 0.351-0.589 while the weight of the tables
ranges 599-603mg/tablet.
In vitro dissolution study
Dissolution study of the prepared doxophylline matrix tablet was
carried out for 12 hours.(Fig. 2 and 3) From the release profile we
can see that batches F1 to F6 shows release of drug more than 15%
at first hour. The % drug release after 12 hours for formulation F1,
F3, F4 was found to be 84.62, 94.58 and 89.6.85 respectively.
Accelerated stability study of best batch (F3)
Stability study was carried out for 3 months. sample withdraws at
the interval of one month for three months which showed no change
in in-vitro drug release profile (fig 4). Percentage assay cumulative
release of drug shows 99.89 (initial), 98.51 (after 1 month). 97.36
(after 3months). From the result of the stability study we can
conclude that the doxophylline matrix tablet is stable and shows no
change at 40˚C for extended period of time.
CONCLUSION
Doxophylline sustained release matrix tablet was prepared
successfully using HPMC as polymer to retard release and achieve
required dissolution profile From DSC study, we can show that there
is no change in drug’s melting peak (144.56°C) after the preparation
of tablet. Stability study of batch F3 after three month showed no
change in in-vitro drug release profile. Hence, the optimized
formulations seem to be stable. Based on dissolution studies all the
formulations showed sustained release of drugs from the
formulations. As expected the release rate was slower with higher
viscosities of HPMC. The molecular weight variations in HPMC are
commonly expressed as viscosity grades. Larger viscosity grades
correspond to greater polymer molecular weight. Based on above
studies it can be concluded that developed matrix formulation can
serve as a successful sustained drug delivery system.
ACKNOWLEDGMENT
Author’s are thankful to Shree Devi College of Pharmacy,
Mangalore (India) authority for providing suitable research
laboratory to carry out this project work and it also thanks to Yarrow
Chem. India ltd, India. For providing gift sample of doxophylline,
Materials Research Centre, Indian Institute of Science(IISc),
Bangalore for differential scanning calorimeter.
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Table 1: formulation of doxophylline matrix tablet

INGREDIENTS FORMUL ATION CODE
F1 F2 F3 F4 F5 F6
Doxophylline 400 400 400 400 400 400
HPMC K-4M 25 - 50 - 55 40
HPMC K-100M - 25 - 50 40 40
PVP K-90 15 15 15 15 15 15
MCC(Avicel) 150 150 125 125 95 105
Magnesium 10 10 10 10 10 10
stearate
Total weight of each tablet = 600mg

Table 2: Powder flow properties for formulated physical mixtures

Formulation code Angle of repose* (°) Bulk density* Porosity* Carr’s index*
(g/cm3) (%) (%)

F1 24.85±0.25 0.338±0.005 11.88±0.02 13.14±0.20

F2 20.18±0.19 0.374±0.007 12.14±0.08 12.93±0.78
F3 28.15±0.27 0.366±0.002 12.39±0.09 13.13±0.46
F4 21.58±0.52 0.370±0.001 13.25±0.07 13.80±0.88
F5 29.39±0.98 0.310±0.008 12.75±0.05 14.50±0.29
F6 26.48±0.20 0.381±0.002 13.45±0.05 14.90±0.25
Note: (*) All values are the mean of three readings

Table 3: Physicochemical parameters of developed matrix tablets of doxophylline

Formulation code Hardness* Thickness* Friability* Weight*
(kg/cm2) (mm) (%) (mg)
F1 7.20±0.140 3.91±0.001 0.351 601±1.00
F2 7.50±0.550 3.88±0.004 0.456 602±1.80
F3 8.03±0.120 3.56±0.006 0.421 601±2.30
F4 8.18±0.497 3.28±0.005 0.537 599±1.90
F5 8.60±0.290 3.75±0.003 0.467 603±0.80
F6 8.10±0.107 3.96±0.008 0.589 602±2.50
Note: (*) All values are the mean of three readings

Fig. 1 : DSC Spectra of Doxophylline (A), HPMC K-4M (B), HPMC K-100M (C), PVP K 90(D), Avicel (E), magnesium stearate (F) & physical mixture of
doxophylline with formulation excipients (G)

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(12), 2011

 Pandya Hima V et al. IRJP 2011, 2 (12), 204-207

Fig. 2: In-vitro dissolution profiles release of batches F1 to F3

Fig. 3: In-vitro dissolution profiles release of batches F4 to F6

Fig. 4 : Drug release profile of THP SR matrix tablet before and after stability study of best batch F3

Source of support: Nil, Conflict of interest: None Declared

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(12), 2011